Prevention and therapy of Staphylococcus aureus infections

金黄色葡萄球菌感染的预防和治疗

• 批准号: 8046919
• 负责人: Olaf Schneewind
• 金额: $ 233.51万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046919
• 关键词: Address; Adenosine; Agglutination; Agglutinins; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibodies; Antigen Presentation; Antigens; Apoptotic; Attenuated; B-Lymphocytes; Basic Science; Binding Proteins; Blocking Antibodies; Blood Circulation; Blood Clot; Blood coagulation; Cleaved cell; Coagulase; Coagulation Process; Communicable Diseases; Community Hospitals; Complement; Deposition; Disease; Failure; Fibrin; Fibrinogen; Generations; Genomics; Genotype; Genus staphylococcus; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunosuppression; Infection; Investments; Kinetics; Knowledge; Lead; Lesion; Libraries; Lower respiratory tract structure; Mediating; Membrane Proteins; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Nosocomial Infections; Pathogenesis; Phagocytosis; Phase; Prevention; Prevention therapy; Property; Proteins; Prothrombin; Reporting; Research; Resources; Scientist; Screening procedure; Skin; Soft Tissue Infections; Staphylococcal Infections; Staphylococcal Protein A; Staphylococcal Vaccines; Staphylococcus aureus; Superantigens; Surface; Technology; Therapeutic; Time; Tissues; Translating; United States National Institutes of Health; Vaccination; Vaccines; Variant; Virulence; design; global health; high throughput technology; human disease; human monoclonal antibodies; human mortality; human subject; improved; in vitro Assay; macrophage; methicillin resistant Staphylococcus aureus; mortality; mutant; neutralizing antibody; neutrophil; new technology; novel; pathogen; prevent; programs; protein expression; public health relevance; quantum; resistant strain; response; tool; vaccine development; von Willebrand Factor

DESCRIPTION (provided by applicant): This proposal addresses Theme 4 (Focusing on global health) of NIH RFA-OD-10-005 by aiming to generate staphylococcal vaccines. The project also addresses Theme 1 (Applying Genomics and Other High Throughput Technologies) through the systematic analysis of human B cell responses as well as Theme 2 (Translating Basic Science Discoveries into New and Better Treatments) through the invention of a novel treatment - therapeutic vaccination - for human MRSA infections. Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the world. Antibiotic resistant strains (MRSA) are isolated in more than half of all community and hospital infections, and humans that survive MRSA infections do not develop protective immunity. We report that MRSA evasion from host protective immune responses is triggered by two surface molecules, adenosine synthase A (AdsA) and protein A (SpA). AdsA produces the immune suppressive molecule adenosine, whereas SpA triggers the apoptotic collapse of B cell immune responses. Studies on host immune responses to challenge with attenuated S. aureus strains and on the immunity elicited from purified staphylococcal subunit antigens lead us to propose that protective immunity against MRSA is achieved via neutralizing antibodies, which block the pathogen's coagulation and agglutination strategies during infection. Enabled by the availability of an exciting new technology - high-throughput isolation of monoclonal antibodies from human plasmoblasts - we propose here the systematic analyses of B cell responses for neutralizing antibodies against staphylococcal AdsA, SpA, coagulases and agglutinins. These antibodies will be used to define the hitherto elusive attribute of protective immunity against MRSA infections using in vitro assays and animal models for staphylococcal diseases. Once endowed with such information, we will generate immune therapeutics for the treatment of MRSA infections and vaccines to globally prevent staphylococcal infections. This ARRA proposal represents a one-time investment into a unique knowledge gap and a technological opportunity with a probable quantum yield of returns in translational products. Beyond its initial phase of discovery, this research program is designed to attract private resources leading to the development of vaccines that can protect humans from disease and thereby improve Global Health. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus, in particular antibiotic resistant isolates (MRSA), are a leading cause of infectious disease morbidity and mortality in the world. However, vaccines or immune therapeutics against MRSA are not available. During staphylococcal infection, protein A, coagulase and von-Willebrand-Factor binding-protein impart toxic functions on blood clotting or immune suppression that can be overcome through the generation of specific immune responses directed against these factors. These technologies will be developed with the goal of generating a vaccine and immune therapeutics, thereby providing protection against S. aureus infections and improving global health.

描述（由申请方提供）：本提案旨在生产葡萄球菌疫苗，以解决NIH RFA-OD-10-005的主题4（关注全球健康）。该项目还通过对人类B细胞反应的系统分析解决了主题1（应用基因组学和其他高通量技术），并通过发明一种新的治疗方法-治疗性疫苗接种-解决了主题2（将基础科学发现转化为新的更好的治疗方法）。 金黄色葡萄球菌是世界上引起血液、下呼吸道、皮肤和软组织感染的主要原因。抗生素耐药菌株（MRSA）在超过一半的社区和医院感染中被分离出来，并且在MRSA感染中存活的人不会产生保护性免疫力。我们报告说，MRSA逃避宿主保护性免疫反应是由两个表面分子，腺苷合成酶A（AdsA）和蛋白A（SpA）。AdsA产生免疫抑制分子腺苷，而SpA触发B细胞免疫应答的凋亡崩溃。减毒沙门氏菌攻击后宿主免疫应答的研究。金黄色葡萄球菌菌株和纯化的葡萄球菌亚单位抗原引起的免疫力，使我们提出，通过中和抗体，这阻断了病原体的凝血和凝集策略感染期间实现对MRSA的保护性免疫。通过一个令人兴奋的新技术的可用性-高通量分离单克隆抗体从人浆细胞-我们建议在这里的B细胞的反应，对葡萄球菌AdsA，SpA，凝固酶和凝集素的中和抗体的系统分析。这些抗体将用于定义迄今为止难以捉摸的属性的保护性免疫，对MRSA感染，使用体外试验和动物模型的葡萄球菌疾病。一旦获得这些信息，我们将开发出治疗耐甲氧西林金黄色葡萄球菌感染的免疫疗法和全球预防葡萄球菌感染的疫苗。这项ARRA提案代表了对一个独特的知识差距和一个技术机会的一次性投资，在转化产品中可能产生量子收益。除了最初的发现阶段，该研究计划旨在吸引私人资源，以开发可以保护人类免受疾病侵害的疫苗，从而改善全球健康。 公共卫生相关性：金黄色葡萄球菌（Staphylococcus aureus），特别是抗生素抗性分离株（MRSA），是世界上传染病发病率和死亡率的主要原因。然而，针对MRSA的疫苗或免疫治疗剂不可用。在葡萄球菌感染期间，蛋白A、凝固酶和von-Willebrand-因子结合蛋白对血液凝固或免疫抑制赋予毒性功能，这些毒性功能可以通过产生针对这些因子的特异性免疫应答来克服。这些技术将被开发，目标是产生疫苗和免疫疗法，从而提供针对S。金黄色葡萄球菌感染和改善全球健康。